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The aim of our study is to evaluate effects of early rehabilitation treatment in hospitalized patients with severe COVID-19, in order to improve patients’ autonomy and quality of life. This observational study has been performed in hospitalized patients with severe COVID-19. All patients were evaluated at T0 using specific scales: Modified Barthel Index (MBI) for autonomy in ADL, Mini Mental State Examination (MMSE) for cognitive status, Borg scale for dyspnoea, EQ5D scale for quality of life. In absence of contraindications for the rehabilitation treatment, patients start early a rehabilitation protocol consisting of one session (30 minutes) per day, for 2 to 3 weeks; these scales have been repeated at patient’s demission (T1). 70 patients (37 women and 33 men, with average age of 71 years) with severe COVID-19 were included in the study. After rehabilitation treatment, MBI increases statistically significantly from T0 to T1 (39.8±35.0 with 95% CI 31.6–48, vs 69.8±38.1 with 95% CI 60.8–78.7, p < 0.001); besides MBI at T0 correlates inversely and statistically significantly with all EQ-5D variables at T0, similarly at T1 (p < 0.001), indicating the improvement of autonomy and therefore of the quality of life. The MMSE correlates statistically significantly with MBI at T0 and T1 (r = 0.569, r = 0.747 respectively, p < 0.001), indicating that an adequate cognitive status is connected with a greater increase in autonomy in ADL after rehabilitation treatment. MBI correlates directly and significantly with the PaO2/FiO2 value both at T0 and T1 (r = 0.263 with p = 0.039, r = 0.389 with p = 0.023 respectively), indicating that improving the oxygen exchanges also improves the patient’s autonomy. An early rehabilitation treatment should promote autonomy and a better quality of life in patients with COVID-19.